Parkinson's disease (PD) is a neurodegenerative disorder, which is the most common age-related disorder after Alzheimer's [1]. The affected patients show neuronal death in particular brain regions, i.e., pars compacta of substantia nigra and ventral tegmental, resulting in depletion of brain dopamine levels [2,3]. PD affects millions globally [4], and the number of people affected proportionate with increasing age [5]. Since last century, the PD prevalence rate has increased by 117.8% and death rates by 149.8% [6]. The cost of PD management is a substantial economic burden for many countries. In the USA, direct and indirect expenses of PD are estimated to be 51.9 billion dollars per year, comprising treatment costs, caregiver expenditures, and loss of income [7]. This economic burden is projected to cross 79 billion dollars by 2037 [7]. PD also severely impacts patients' quality of life [8]. Studies showed that PD patients face one of the worst mental, physical, and social impacts on their life [[9], [10], [11]].

The leading causes of PD manifestation are oxidative stress, defective proteolysis, genetic factor, mitochondrial dysfunction, aggregation, toxicity, and misfolding of α-synuclein protein [[12], [13], [14], [15]]. A recent clinical study assessed the performance of α-synuclein seed amplification assays as a biochemcial diagnostic tool for PD identification [[16], [17]]. The α-synuclein seed amplification assays was highly selective and specific in PD diagnosis. The head injury can also be a prompting factor for the disease progression [18,19]. PD symptoms are classified into two types: motor and non-motor. Motor symptoms are bradykinesia, rigidity, and tremor, and non-motor symptoms are depression, cognitive dysfunction, hyposmia, hallucinosis, and sleep disorders [20,21]. The current PD drug therapy includes dopamine precursors, dopamine agonists, or dopamine degradation inhibitors like catechol-o-methyltransferase (COMT) and monoamine oxidase-B (MAO-B) inhibitors [22]. These drugs provide symptomatic relief for motor symptoms. However, these therapies have challenges, such as high therapeutic doses, frequent administration, high first-pass metabolism, enzymatic degradation, organ toxicity, and poor brain availability due to blood-brainp barrier (BBB). Further, the brain-targeted delivery systems are still limited for PD management. Therefore, there is a need to develop better delivery approaches for available antiparkinson drugs, providing direct delivery to the brain and reduce side effects. BBB poses a major hurdle in the treatment that restricts the entry of most drugs into the brain. Several strategies have been explored to deliver drugs directly to the brain by avoiding BBB. These strategies can be classified as invasive and non-invasive. Invasive techniques include chemical disruption of BBB [23], convection-enhanced delivery [[24], [25], [26]], polymeric wafers, and microchip technologies [27]. The non-invasive approaches include efflux pump inhibition [28,29], prodrug approaches [[30], [31]], targeted nanocarrier-based drug delivery [[32], [33], [34]], cell-based therapy [35], and intranasal drug delivery systems [[36], [37], [38]].

Nose-to-brain (N2B) drug delivery is transmucosal delivery that avoids BBB, unlike the systemic route. Intranasal administration overcomes several problems of oral administration, such as avoidance of hepatic first-pass metabolism, gastrointestinal enzymatic degradation, and systemic toxicity [24,39,40]. Further, the intranasal delivery shows the rapid absorption and rapid onset of action [41], enhanced therapeutic effects without systemic exposure and reduced peripheral organ toxicity. The absolute absence of any pain and ease of self-administration make this delivery approach patient-friendly for PD. However, intranasal drug delivery also has many challenges. These challenges include poor permeation of hydrophilic drugs, enzymatic degradation in the nasal cavity, mucociliary clearance, shorter residence time, and improper administration [41]. These prime problems could effectively be addressed by using suitable nanocarrier-based intranasal formulations. Intranasal nanocarrier-based systems for brain delivery allow easy crossing of the therapeutic actives through the nasal mucosal membrane [42]. The favorable properties of the nanocarriers, such as size, shape, and charge facilitate their direct entry into the brain via the olfactory pathway [43]. Several clinical and preclinical studies have demonstrated that intranasal administration of nanocarriers has successfully improved the efficiency of antiparkinson drugs. Specifically, surface-modified nanocarriers can help in better brain targeting, reduce unwanted drug distribution to other organs, and lower toxicity.

This review presents the recent developments of nanocarrier-based N2B delivery systems for effective managment of PD. The potential disease targets, nanocarriers' intranasal absorption pathways, and transport mechanisms to the brain have been discussed. The clinical trials of intranasal antiparkinson drugs, safety aspects concerning nasal physiology, nanocarriers, and nanocarrier excipients are also discussed.